Accomplishments: AIM 1:Although the aggressiveness of IBC is well known, there is no clear clinicopathologic profile for this tumor type, often making diagnosis difficult. One goal of our study is to develop a clinicopathological diagnosis of IBC by using the anonymyzed data and correlating it with molecular markers expressed by the tumors. The Inflammatory Breast Cancer Registry and Biospecimen Repository is a project funded by a grant from the Department of Defense to Dr. Paul H. Levine (George Washington University Medical Center - GWUMC). The purpose of the registry is to develop a national registry of patients with IBC that will contain standardized clinical, epidemiological, and pathological information, along with recurrence and survival data. Investigators at GWUMC consented recruited patients and collected clinical data. We obtained tumor blocks from 132 patients with IBC from the Registry and cut 10 slides from each block. We obtained 150 non-IBC stage matched specimens from the Cooperative Breast Cancer Tissue Resource (CBCTR) to be used as control tissue. IBC cases identified in a national IBC registry (1991- 2005) and non-IBC breast cancer control cases (stage III and age-matched) from the NCI Co-operative Breast Cancer Tissue Resource are used in this study. In an exploratory fashion, the protein levels of certain biomarkers are evaluated by using immunohistochemical (IHC) staining. These markers are selected to investigate cellular growth and differentiation, cell adhesion/invasion, and angio-lymphangiogesis. The goal is to determine the prevalence of elevated levels in these samples, compare values between patients with and without IBC, and investigate the relationship of these levels to survival. We have evaluated the expression of estrogen receptor (ER), E-cadherin and podoplanin. E-cadherin expression was quantitatively analyzed using an Automated Cellular Imaging System. Using podoplanin IHC, we further defined lymph vascular density (LVD) and intra-lymphatic tumor emboli (ILTE). We found that IBC was significantly related to E-cadherin expression, high tumor grade and ILTE. We are currently in the process evaluating expression of other proteins to identify IBC-specific biomarkers such as vascular endothelial growth factor (VEGF) C, VEGF D, and VEGFR2. Dr. Levine's group is working ot obtain all the updated clinical informatinon. Aim 2: A pilot study of BV in patients with IBC completed accrual or 21 patients. There was a significant decrease in tumor-associated phospho-KDR expression, and increase in tumor apoptosis and a decrease in vascular permeability by MRI after BV treatment alone. In responding patients, there were trends toward decreased VEGF expression after BV alone and decreased tumor cell proliferation after BV and chemotherapy.Bevacizumab has inhibitory effects on VEGF receptor activation and vascular permeability, and induces apoptosis in tumor cells. A decrease of 66.7% in phospho-KDR and an increase in 128.9% of tumor apoptosis occured following the first cycle of bevacizumab. A trend towards decreasing endothelial cell prolifersion was also apparent. A median decrease of tissue VEGF of 50% was found. In addition, DCE-MRI can be used to reliably detect the biolgic effects of bevacizumab. There was a decrease in GKM Ktrans, Kep, and AUC of DCE-MRI following bevacizumab administration. Heuristic slope wash in decreased 60% for responders and only 30% for non-responders. The second study started a few months ago with two patients accrued to date. Cardiotoxicity was seen, grade 2 asymptomatice, in both patients so the study has been put on hold. An ammendment is being written to change the treatment regimen to anthracycline followed by a taxane and AZD2171. The third study is still open to accrual with 4 patients accrued at the NCI. The goal is to complete this study and then participate in a randomized phase III study in IBC.